Scientists from IAVI and Scripps Research have achieved a significant breakthrough in HIV vaccine development, demonstrating that a targeted vaccine strategy can successfully activate and advance crucial immune responses needed to combat the virus. The findings, published in Science on May 15, 2025, combine data from two separate phase 1 clinical trials involving nearly 80 participants from North America and Africa.
The research addresses one of the most persistent challenges in HIV vaccine development: training the immune system to produce antibodies capable of targeting the virus's many variants. HIV's rapid mutation rate and ability to hide key components from immune detection have historically thwarted traditional vaccine approaches.
Stepwise Vaccination Strategy Shows Promise
The first trial, IAVI G002 conducted in North America, tested a stepwise vaccination strategy using heterologous boosting—where a priming dose and a distinct booster dose are administered sequentially to guide the immune system through stages of antibody development.
"We've now shown in humans that we can initiate the desired immune response with one shot and then drive the response further forward with a different second shot," explains senior author William Schief, professor of immunology and microbiology at Scripps Research and executive director of vaccine design at IAVI's Neutralizing Antibody Center.
All 17 participants who received both the priming vaccine and the booster developed VRC01-class antibody responses—early immune defenses with key features of broadly neutralizing antibodies (bnAbs). More impressively, over 80% showed "elite" responses, meaning their immune cells acquired multiple helpful mutations linked to bnAb development.
The second trial, IAVI G003, focused solely on the priming stage and was conducted in South Africa and Rwanda—countries among those most affected by HIV in sub-Saharan Africa. This trial demonstrated that the initial vaccine dose could successfully activate the desired immune cells in African participants, with 94% developing VRC01-class responses.
mRNA Platform Enables Faster Development
Both trials utilized an mRNA-based vaccine platform similar to the technology used in COVID-19 vaccines. This approach enabled faster production and clinical testing while providing strong immune responses.
"These remarkable results validate the rational vaccine design that underpins this approach," says Mark Feinberg, President and CEO of IAVI. "A vaccine would be a tremendous step forward for global health and could help bring an end to the HIV pandemic."
Targeting Broadly Neutralizing Antibodies
Broadly neutralizing antibodies (bnAbs) are rare immune defenses that can recognize and block a wide range of HIV variants by targeting parts of the virus that remain constant despite mutations. Scientists have long viewed bnAbs as the immune system's best chance at preventing HIV infection.
The vaccine strategy employs germline targeting—using a priming vaccine to activate rare B cells with the potential to eventually produce bnAbs. Later booster doses guide these cells through maturation toward producing HIV-targeting antibodies.
"What really surprised us was the quality of the immune response we saw after just two shots—one prime and one heterologous boost," says Schief. "We didn't anticipate it would be that favorable."
Global Potential Demonstrated
Crucially, the immune responses were remarkably similar between participants in Africa and North America, supporting the potential for a globally effective vaccine.
"These incredibly exciting results underscore the importance and capability of global partnerships to drive cutting-edge science," says Julien Nyombayire, executive director of the Center for Family Health Research in Kigali, Rwanda, and one of the lead principal investigators of G003. "It was essential to conduct this evaluation in African populations to ensure that our results reflect the safety and immunologic data from high-burden communities who would deeply benefit from an HIV vaccine."
Safety Profile and Next Steps
The vaccine regimen was generally well tolerated, though some skin reactions were observed. In G002, 18% of participants experienced reactions such as itching and hives, with 10% developing chronic urticaria lasting six weeks or longer. These events were typically mild or moderate and all eventually resolved. The G003 trial saw no cases of urticaria, though two participants experienced mild, short-lived itching.
A follow-up study is planned in South Africa to evaluate the same prime-boost approach tested in G002, but at a lower dose, building on the elite responses seen in the boosted group.
Collaborative Research Effort
This breakthrough represents the culmination of extensive collaboration between scientific research institutions, funders, private sector partners, and governments. Moderna partnered in both trials, providing the mRNA vaccines and support for preclinical development and regulatory filings.
The work builds on earlier research from Schief's lab, including results published in 2022 from the IAVI G001 clinical trial and a series of preclinical studies published in 2024 that demonstrated how a multi-step vaccination strategy could guide the immune system toward producing protective antibodies.
While these trials weren't intended to generate fully mature bnAbs, they provide compelling evidence that the stepwise approach to guiding the immune system toward producing these powerful antibodies has great promise—not just for HIV vaccines but potentially for other challenging infectious diseases as well.
"We also now have a better idea of what kinds of immune cells we need to target to keep moving the response forward," Schief notes, highlighting the pathway for continued advancement in this critical area of vaccine research.
